Flavonoids are abundant in edible plants and possess a wide variety of biological activities, including antioxidant, anti-carcinogenic, antibacterial, anti-fungal activities, and also may play a role in preventing infectious diseases.1,2 One class of flavonoids, the chalcones, are known to inhibit enzymes such as 15-hydroxy-prostaglandin dehydrogenase1a, 5-lipoxygenase3, cyclooxygenase4 and protein tyrosine phosphatase 1B5. Thus, chalcone-based drugs are potential tools for the treatment of gastric lesions′, asthma, inflammation and allergies4, as well as type 2 diabetes and obesity5.
In 2004, xanthohumol 1 (shown in FIG. 1), a prenylated chalcone derived from hops, showed moderate antiviral activity against several herpes viruses, including human cytomegalovirus (HCMV).6 In addition to viral signaling, inhibitors of pro-growth signaling cascades could also have applications in human cancer. For example, xanthohumol and butein 2 (a related tetrahydroxychalcone shown in FIG. 1) downregulate the CXCR4 chemokine receptor and inhibit tumor growth.7,8 Another related chalcone flavonoid, isoliquiritigenin, which was shown to inhibit the growth of prostate cancer cells, induce cell cycle arrest and apoptosis in lung cancer cells and exhibit anti-estrogenic activity towards breast cancer cells.9 
Chemokine receptors are heptahelical G protein-coupled receptors (GPCRs) that bind chemokines (i.e., small chemotactic cytokines, critical for recruiting and activating cells of the immune system during inflammation). Butein 2 prevents interaction between the CXCR4 chemokine receptor and its endogenous ligand chemokine CXCL12, which has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation.10 Butein prevents binding of CXCL12 to both its receptors, CXCR7 and CXCR4, but does not prevent the binding of other CXCR4 ligands, like CCL5 and CXCL8, to their receptor. These observations suggest that this chalcone may actually bind to the CXCL12 chemokine rather than its receptor, CXCR4.10 
The US28 receptor is one of the viral G-protein coupled receptors (vGPCRs) encoded in double stranded DNA of Human Cytomegalovirus (HCMV). It possesses high homology with human chemokine receptors. For example, US28 has 30% and 28% amino acid sequence homology with the human CCR1 and CXCR3 receptor, respectively.11 This similarity enables efficient coupling to signaling networks of the infected host.12 The US28 receptor possesses the ability to bind different human CC-chemokines (including CCL5/Rantes), as well as the CX3C-chemokine CX3CL1/Fractalkine. Similar to other vGPCRs, the US28 receptor is also characterized by ligand-independent signaling. In fact, US28 constitutive signaling enables virus survival, host invasion and, in some cases, oncogenesis or cardiovascular disease, by exploiting preferred signaling cascades.13 HCMV establishes a lifelong persistent/latent infection in immuno-competent hosts and can lead to severe and life-threatening diseases in patients with immature or suppressed immune systems.14,15 Thus, the US28 receptor may play a role in viral dissemination and persistence, as well as a role in cardiovascular disease and tumorigenesis.15,16 
Recent studies have looked at the specific mechanism of action of the following two flavonoids on viral properties such as transcription factor activation, receptor tyrosine kinase activity, and nuclear translocation. Baicalein 3 has been shown to have activity against HCMV by preventing viral entry. This is accomplished by targeting the kinase activity of EGFR, which is required for HCMV entry and cellular activation.17 Quercetin 5, on the other hand, was shown to inhibit HIV-1 integrase, which mediates the insertion of viral DNA into host cellular DNA. Quercetin is also essential for viral replication and virion production.18 To date, some chalcones and flavonoids have been assessed for their ability to interact with the US28 receptor, but their efficacy needs improvement prior in vivo usage. Compounds 5a-d represent the other known US-28 receptor inverse agonists which are not predicated upon flavones architectures.